1. Field of the Invention
The present invention is directed to various taxols, the process for preparing the same and novel intermediates thereof. In addition, the present invention relates to 2,5-dihydroxy-2-patchoulenes, which is not only a "bottleneck" intermediate in the synthesis of taxols but is also a flavoring agent.
2. Background of the Invention
In recent years, taxol has attracted much interest in both the biological and chemical arts. Taxol is a member of the taxane family of diterpenes, having the structure shown below: ##STR1## This compound was reported by Wani et al. in JACS, 93, 2325, (1971) to exhibit significant anti-tumor properties. More specifically, taxol shows strong cytotoxicity in KB cell structures and in several of the National Cancer Institute's in vivo screens, including P-388, L-1210 and P-1534 mouse leukemias, the B-16 melanocarcinoma, the CX-1 colon xenograft, the LX-1 lung xenograft and the MX-1 breast xenograft. In addition, taxol blocks cell replication in HeLa cells, especially in the mitotic phase of cell division. More specifically, it has been reported by Schiff et al in Nature, 277, 665 (1979) that taxol promotes the assembly of microtubule proteins responsible for the formation of spindles during cell division.
Because of its promising anti-cancer activity and its unusual structure and mechanism of action, taxol represents a prototype of a new class of chemotherapeutic agents. Consequently, it is presently undergoing clinical trials in both France and the United States.
Taxol is a natural product, which unfortunately is found in minute quantities in only the Taxus brevifolia species such as the Pacific yew tree and the Taxus brevifolia Nutt, from which it was first isolated. As more and more clinical experimentation is performed using taxols, it is becoming increasingly necessary to destroy more and more trees of the taxus species in order to isolate the compound. Consequently, there is a worldwide concern about the survival of the taxus species.
In view of the fact that taxol has significant commercial potential and there is a limited supply of taxol which is slowly being depleted, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxols. However, attempts have been unsuccessful. One difficulty in the synthesis lies in the preparation of the tricyclic carbon frame, pentadecene, which is shown below: ##STR2##
Robert Holton, in Jacs 106, 5731 (1984) reported the synthesis of taxanes A and B through the following scheme: ##STR3##
The major difficulty in the synthesis of taxol and other potential antitumor agents is the incorporation of the plethora of oxygen substituents present at positions 1, 2, 4, 5, 7, 9 and 10 of the ring system. It is believed that the key unlocking the mystery in the synthesis of taxols would be the discovery of a key intermediate. Through the use of this intermediate, it would be possible to form the paentadiene ring having a wide variety of different substituents at various positions. Consequently, the synthesis of taxols would be greatly facilitated. This need has been fulfilled by the discovery of the key intermediate by the present investigators.